Immunogenicity and safety of an MF59-adjuvanted cell-derived higher-dose quadrivalent influenza vaccine (aQIVc) in adults aged 50 years or older: a phase 3 randomised controlled trial.

Background

Combining the benefits of adjuvant, cell-based manufacturing and a higher dose of antigen could boost immune responses in older adults. We aimed to evaluate the immunogenicity and safety of an MF59-adjuvanted cell-derived higher-dose quadrivalent influenza vaccine (aQIVc) compared with MF59-adjuvanted egg-derived quadrivalent influenza vaccine (aQIV) and recombinant quadrivalent influenza vaccine (QIVr) in adults aged 50 years or older.

Methods

This phase 3, randomised, observer-blind, parallel-group, multicentre study randomly assigned (3:2:2) healthy adults aged 50 years or older to aQIVc, aQIV, or QIVr via an interactive response technology system, using a permuted block randomisation method (block size of seven), with stratification by age group (50-64 or ≥65 years), history of any influenza vaccination (previous three influenza seasons), and study site. aQIVc contains haemagglutinin (HA; 45 μg per strain) and MF59 (19·5 mg squalene); aQIV contains 15 μg HA per strain and MF59 (9·75 mg squalene); and QIVr contains 45 μg HA per strain. Participants received one vaccine dose (day 1; intramuscular injection). Primary immunogenicity objectives were lot-to-lot consistency of three batches of aQIVc (met if the 95% CI of the day-29 geometric mean titre [GMT] ratios was 0·67-1·5 for the pairwise comparison of each vaccine strain) and non-inferiority of aQIVc versus aQIV and QIVr (met if the lower bound 97·5% CI for day-29 GMT ratio and seroconversion rate differences were 0·67 or higher and -10% or higher, respectively, per strain) in the per-protocol set. Safety was assessed through solicited (days 1-7) and unsolicited (days 1-29) adverse events, with a subset of unsolicited adverse events collected until end of study (day 365). This trial was registered with ClinicalTrials.gov (NCT06015282).

Findings

Between Nov 3, 2023, and Jan 30, 2024, 7699 adults aged 50 years or older were randomly assigned, of whom 7677 were included in the all exposed set (aQIVc, n=3283; aQIV, n=2205; QIVr, n=2189; as randomised) and 7419 were in the per-protocol set (aQIVc, n=3175; aQIV, n=2129; QIVr, n=2115). Lot-to-lot consistency criteria were fully met. aQIVc was non-inferior and superior (lower bound 97·5% CI of day-29 GMT ratio was more than 1·0; secondary objective) to aQIV at day 29: GMT ratio was 1·53 (97·5% CI 1·43 to 1·64) for A/H1N1, 1·22 (1·15 to 1·30) for A/H3N2, 1·73 (1·63 to 1·85) for B/Victoria, and 1·71 (1·63 to 1·80) for B/Yamagata, and corresponding seroconversion rate differences were 16·8% (97·5% CI 13·9 to 19·8), 9·5% (6·4 to 12·5), 21·9% (18·8 to 24·9), and 24·3% (21·3 to 27·2), respectively. Compared with QIVr, non-inferiority criteria were met for three strains, but not A/H3N2: GMT ratio was 0·93 (97·5% CI 0·87 to 1·00) for A/H1N1, 0·69 (0·65 to 0·74) for A/H3N2, 1·41 (1·33 to 1·50) for B/Victoria, and 1·33 (1·27 to 1·40) for B/Yamagata, and seroconversion rate differences were 1·5% (97·5% CI -1·2 to 4·3), -7·4% (-10·3 to -4·6), 11·6% (8·5 to 14·7), and 13·4% (10·3 to 16·5), respectively. aQIVc was well tolerated; despite higher rates of local and systemic adverse events versus aQIV and QIVr, most were mild-to-moderate, transient, and self-resolved. Serious adverse events were low across all vaccine groups (days 1-181; 91 [2·8%] of 3282 with aQIVc; 78 [3·5%] of 2204 with aQIV; and 64 [2·9%] of 2191 with QIVr).

Interpretation

In adults aged 50 years or older, aQIVc was non-inferior and superior to aQIV for all four influenza strains and non-inferiority criteria for aQIVc versus QIVr were met for A/H1N1 and both B strains, but not A/H3N2. No safety concerns were identified.

Funding

CSL Seqirus.